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Obesity and metabolic syndrome are associated with glomerulosclerosis and proteinuria, but the mechanisms are not known. The purpose of this study was to determine if there is altered renal lipid metabolism and increased expression of sterol regulatory element-binding proteins (SREBPs) in a model of diet-induced obesity. C57BL/6J mice that were fed a high fat, 60 kcal % saturated (lard) fat diet (HFD) developed obesity, hyperglycemia, and hyperinsulinemia compared with those that were fed a low fat, 10 kcal % fat diet (LFD). In contrast, A/J mice were resistant when fed the same diet. C57BL/6J mice with HFD exhibited significantly higher levels of renal SREBP-1 and SREBP-2 expression than those mice with LFD, whereas in A/J mice there were no changes with the same treatment. The increases in SREBP-1 and SREBP-2 expression in C57BL/6J mice resulted in renal accumulation of triglyceride and cholesterol. There were also significant increases in the renal expression of plasminogen activator inhibitor-1 (PAI-1), vascular endothelial growth factor (VEGF), type IV collagen, and fibronectin, resulting in glomerulosclerosis and proteinuria. To determine a role for SREBPs per se in modulating renal lipid metabolism and glomerulosclerosis we performed studies in SREBP-1c–/– mice. In contrast to control mice, in the SREBP-1c–/– mice with HFD the accumulation of triglyceride was prevented, as well as the increases in PAI-1, VEGF, type IV collagen, and fibronectin expression. Our results therefore suggest that diet-induced obesity causes increased renal lipid accumulation and glomerulosclerosis in C57BL/6J mice via an SREBP-1c-dependent pathway. Obesity and metabolic syndrome are associated with glomerulosclerosis and proteinuria, but the mechanisms are not known. The purpose of this study was to determine if there is altered renal lipid metabolism and increased expression of sterol regulatory element-binding proteins (SREBPs) in a model of diet-induced obesity. C57BL/6J mice that were fed a high fat, 60 kcal % saturated (lard) fat diet (HFD) developed obesity, hyperglycemia, and hyperinsulinemia compared with those that were fed a low fat, 10 kcal % fat diet (LFD). In contrast, A/J mice were resistant when fed the same diet. C57BL/6J mice with HFD exhibited significantly higher levels of renal SREBP-1 and SREBP-2 expression than those mice with LFD, whereas in A/J mice there were no changes with the same treatment. The increases in SREBP-1 and SREBP-2 expression in C57BL/6J mice resulted in renal accumulation of triglyceride and cholesterol. There were also significant increases in the renal expression of plasminogen activator inhibitor-1 (PAI-1), vascular endothelial growth factor (VEGF), type IV collagen, and fibronectin, resulting in glomerulosclerosis and proteinuria. To determine a role for SREBPs per se in modulating renal lipid metabolism and glomerulosclerosis we performed studies in SREBP-1c–/– mice. In contrast to control mice, in the SREBP-1c–/– mice with HFD the accumulation of triglyceride was prevented, as well as the increases in PAI-1, VEGF, type IV collagen, and fibronectin expression. Our results therefore suggest that diet-induced obesity causes increased renal lipid accumulation and glomerulosclerosis in C57BL/6J mice via an SREBP-1c-dependent pathway. Obesity is a known risk factor for cardiovascular disease (1U. S. Department of Health and Human Services JAMA. 1996; 276: 522PubMed Google Scholar) and type-2 diabetes mellitus (2Kissebah A.H. Vydelingum N. Murray R. Evans D.J. Hartz A.J. Kalkhoff R.K. 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World Health Organization, Department of Noncommunicable Disease Surveillance, Geneva1999: 1-59Google Scholar). The metabolic syndrome, which is characterized by the concurrent existence of obesity, dyslipidemia, hyperglycemia, hyperinsulinemia, and hypertension, has been shown to be a strong and independent risk factor for cardiovascular, and all cause mortality (6Lakka H.M. Laaksonen D.E. Lakka T.A. Niskanen L.K. Kumpusalo E. Tuomilehto J. Salonen J.T. JAMA. 2002; 288: 2709-2716Crossref PubMed Scopus (4048) Google Scholar, 7Isomaa B. Almgre P. Tuomi T. Forsen B. Lahti K. Nissen M. Taskinen M.R. Groop L. Diabetes Care. 2001; 24: 683-689Crossref PubMed Scopus (3873) Google Scholar) as well as the development of microalbuminuria and chronic kidney disease (8Chen J. Muntner P. Hamm L.L. Jones D.W. Batuman V. Fonseca V. Whelton P.K. He J. Ann. Intern. Med. 2004; 140: 167-174Crossref PubMed Scopus (1139) Google Scholar). 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Transplant. 2002; 17: 1157-1159Crossref PubMed Scopus (125) Google Scholar). Although incompletely understood, several hemodynamic, hormonal, and metabolic factors have been proposed to contribute to the pathogenesis of nephropathy associated with metabolic syndrome, including intrarenal hypertension and hyperfiltration, oxidative stress, angiotensin II, inflammatory cytokines, hyperinsulinemia/insulin resistance, hyperglycemia/diabetes, and abnormal lipid metabolism (3Abrass C.K. J. Am. Soc. Nephrol. 2004; 15: 2768-2772Crossref PubMed Scopus (70) Google Scholar, 9Bagby S.P. J. Am. Soc. Nephrol. 2004; 15: 2775-2791Crossref PubMed Scopus (227) Google Scholar, 11Praga M. Nephrol. Dial. Transplant. 2002; 17: 1157-1159Crossref PubMed Scopus (125) Google Scholar, 12Wisse B.E. J. Am. Soc. Nephrol. 2004; 15: 2792-2800Crossref PubMed Scopus (759) Google Scholar, 13Guan Y. J. Am. Soc. Nephrol. 2004; 15: 2801-2815Crossref PubMed Scopus (158) Google Scholar, 14El-Atat F.A. Stas S.N. McFarlane S.I. Sowers J.R. J. Am. Soc. Nephrol. 2004; 15: 2816-2827Crossref PubMed Scopus (166) Google Scholar). Historically, Virchow (15Virchow R. Cellular Pathology, as Based upon Physiological and Pathological Histology.2nd. Robert M. Dewitt, NY1860: 383-408Google Scholar) first suggested the association between lipids and renal disease in 1858 when he described successive stages of fatty metamorphosis and fatty detritus in the renal epithelium in Bright's disease. In their classic paper in 1936 describing the pathological sign of nodular sclerosis Kimmelstiel and Wilson (16Kimmelstiel P. Wilson C. Am. J. Pathol. 1936; 12: 83-98PubMed Google Scholar) also demonstrated the presence of lipid deposits in the kidneys of diabetic patients, and they suggested that these lipids play an important role in the pathogenesis of renal disease. Since then several studies in human subjects and in experimental animals with diabetes have shown a correlation between serum lipids, renal lipids, and proteinuria and progressive decline in renal function (17Spencer M.W. Muhlfeld A.S. Segerer S. Hudkins K.L. Kirk E. LeBoeuf R.C. Alpers C.E. Am. J. Nephrol. 2004; 24: 20-31Crossref PubMed Scopus (44) Google Scholar, 18Bonnet F. Cooper M.E. Diabetes. Metab. 2000; 26: 254-264PubMed Google Scholar, 19Gin H. Rigalleau V. Aparicio M. Diabetes Metab. 2000; 26: 45-53PubMed Google Scholar, 20Sun L. Halaihel N. Zhang W. Rogers T. Levi M. J. Biol. Chem. 2002; 277: 18919-18927Abstract Full Text Full Text PDF PubMed Scopus (274) Google Scholar). Our previous work has suggested that renal lipid accumulation associated with increased renal lipid synthesis is involved in the nephropathy seen in the type I diabetes animal model (20Sun L. Halaihel N. Zhang W. Rogers T. Levi M. J. Biol. Chem. 2002; 277: 18919-18927Abstract Full Text Full Text PDF PubMed Scopus (274) Google Scholar). Whether a similar alteration in renal lipid metabolism and accumulation of lipids mediates the kidney disease associated with obesity-initiated metabolic syndrome, however, has not been established. In recent years the sterol regulatory element-binding proteins (SREBPs) 2The abbreviations used are: SREBP, sterol regulatory element-binding proteins; ACC, acetyl-CoA carboxylase; FAS, fatty acid synthase; PAI-1, plasminogen activator inhibitor-1; VEGF, vascular endothelial growth factor; LFD, low fat, 10 kcal % fat diet; HFD, high fat, 60 kcal % saturated (lard) fat diet; ECM, extracellular matrix; HMG, hydroxymethylglutaryl; ABCA1, ATP-binding cassette A-1; ACO, acetyl-CoA oxidase; PAS, periodic acid Schiff. have been shown to be master regulators of both fatty acid and cholesterol metabolism. Three SREBP isoforms, SREBP-1a, SREBP-1c, and SREBP-2, have been identified and characterized. SREBPs are synthesized as precursors bound to the endoplasmic reticulum. After a two-step cleavage process, the N-terminal segment of SREBP, also referred to as the mature (active) form, is released the membrane and the to of to SREBP-1 involved in fatty acid whereas SREBP-2 involved in cholesterol Biol. PubMed Scopus Google Scholar, J. Clin. 2002; PubMed Scopus Google Scholar). Although the role of SREBP in has been in and S. Y. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar, N. H. A.H. T. T. T. M. S. H. Y. Y. K. J. K. T. R. S. N. J. Biol. Chem. 2002; 277: Full Text Full Text PDF PubMed Scopus Google is known of role in renal the and factors associated with the development and of obesity, diet and have been the of study Kirk M.E. LeBoeuf R.C. Metab. PubMed Scopus Google Scholar, P.K. Am. J. 2000; PubMed Google Scholar, F. B. J. Full Text Full Text PDF PubMed Google Scholar). High saturated fat has been shown to contribute to the development of obesity, hyperglycemia/diabetes, hyperinsulinemia/insulin resistance, and vascular disease in and Full Text PDF PubMed Scopus Google Scholar, 2001; Full Text Full Text PDF PubMed Scopus Google Scholar, J. S. N. C. H.M. PubMed Scopus Google all of which have been in the pathogenesis of renal disease associated with the metabolic The of the study are to in a model of diet-induced obesity there is altered renal lipid metabolism and renal accumulation of lipids, those changes in development of renal sclerosis and proteinuria, and renal expression of SREBPs per se an important role in the pathogenesis of renal disease. were SREBP-1 and SREBP-2 were plasminogen activator inhibitor-1 and vascular endothelial growth factor (VEGF), and were type IV and fibronectin were cell were were first of studies were performed with C57BL/6J and A/J mice the in to the of diet on were in on a and fed low fat, 10 kcal % fat diet high fat, 60 kcal % saturated (lard) fat diet (HFD) for the of mice were in metabolic for to and mice in experimental and were then by of by for and kidney for and lipid of mice in experimental and were and in The kidneys were then for periodic acid and and The of studies was performed in control and SREBP-1c–/– mice the and in animal The of both control and SREBP-1c–/– mice is These mice were also in on a and fed HFD for These studies were by the of the and the of Health experimental the and of mice with National Institutes of Health Blood and was the cholesterol was the cholesterol were by the was a fatty were the was by a via the was by the are as the to and were in with of and were to the of H. 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Chem. 2002; 277: 18919-18927Abstract Full Text Full Text PDF PubMed Scopus (274) Google Scholar). and were for were used for to determine renal accumulation of The kidney were with an and in a by the renal S. were for 10 with in were then with type IV fibronectin in the The were with to for with the to After with the were as a The kidney were then with a are as the for independent were by of and for by for was the HFD and in C57BL/6J but in A/J study the of HFD on obesity, we fed C57BL/6J and A/J mice with HFD for and compared the changes in several of mice. shown in the and kidney of C57BL/6J mice with HFD were increased as compared with those mice with this diet-induced obesity was not in A/J mice. In the and levels were significantly higher in C57BL/6J mice with HFD than in those with A/J mice exhibited no diet-induced and The diet-induced changes in and fatty acid levels were not significant in both C57BL/6J and A/J of of A/J and C57BL/6J mice with C57BL/6J mice with C57BL/6J mice with C57BL/6J mice with cholesterol C57BL/6J mice with fatty acid C57BL/6J mice with in a HFD in C57BL/6J but in A/J study HFD cause an in renal lipid accumulation we performed in kidney which the accumulation of lipids in the glomerular and of C57BL/6J mice There were significant increases in renal triglyceride and cholesterol in C57BL/6J mice with HFD, which well with the increased A/J mice fed a HFD no increases in renal triglyceride and cholesterol and cholesterol in the kidney of A/J and C57BL/6J mice. and cholesterol were in lipid kidney The C57BL/6J mice, not A/J mice, significant increases in renal triglyceride and cholesterol C57BL/6J mice with HFD SREBP-1 and SREBP-2 and in the of C57BL/6J but in A/J we to determine the lipid accumulation in the kidneys of C57BL/6J mice was associated with increased expression of SREBPs are of the of factors that play a role in fatty acid and cholesterol To SREBPs are by to N-terminal their mature and which be the of renal significant increases in SREBP-1 and SREBP-2 in C57BL/6J mice with HFD compared with those mice with In contrast, there were no significant in SREBP-1 SREBP-2 between A/J mice with and HFD The in the renal expression of SREBP-1 was the as HFD significantly increased expression of and SREBP-2 expression a an but there was no expression of and SREBP-2 in the kidneys of C57BL/6J mice with was the kidneys and was synthesized The was the were The C57BL/6J with HFD a significant in the expression of and and a an in the expression of SREBP-2 C57BL/6J mice with HFD of in the of C57BL/6J determine if the increased of SREBP-1 in the of renal we the of that fatty acid acetyl-CoA and fatty acid with C57BL/6J mice with LFD, in those mice with HFD there were significant increases in and which that fatty acid synthesis be increased renal triglyceride also be via fatty acid we the of acetyl-CoA a that mediates fatty acid that to higher in of fatty acid in C57BL/6J mice with HFD that increased SREBP-1 and of fatty acid synthesis the increased triglyceride accumulation in C57BL/6J mice with HFD levels of involved in lipid metabolism in the kidneys of C57BL/6J mice with acid C57BL/6J mice with C57BL/6J mice with acid C57BL/6J mice with C57BL/6J mice with C57BL/6J mice with in a To determine if the increased of SREBP-2 the of that cholesterol we the of a that mediates cholesterol In C57BL/6J mice fed an HFD there was a significant in increased renal cholesterol also be via cholesterol we the of ATP-binding cassette and of cholesterol that the of was increased and a in C57BL/6J mice fed an HFD increased SREBP-2 expression by increased cholesterol synthesis the increased cholesterol accumulation in C57BL/6J mice with HFD HFD and in C57BL/6J but in A/J the of diet-induced obesity on renal we performed the on kidney with C57BL/6J mice with LFD, kidney of C57BL/6J mice with HFD increased which is a of mesangial expansion with increased extracellular matrix of major type IV and fibronectin, were increased in C57BL/6J mice as in the increased expression was in the mesangial matrix is an of In contrast to C57BL/6J mice, A/J mice, which were resistant to diet-induced obesity, no sign of glomerulosclerosis with The glomerular changes in mice fed a HFD were also associated with a significant of which is an of glomerular with of glomerular HFD not cause proteinuria in A/J mice of kidney for fibronectin and type IV of C57BL/6J mice fed a an were used for for fibronectin and type IV In contrast to C57BL/6J mice fed a LFD, there was increased fibronectin and type IV in those mice fed an of A/J and C57BL/6J mice with HFD, as to There was a significant in in C57BL/6J mice with HFD compared with those mice with C57BL/6J with HFD of and in C57BL/6J but in A/J mesangial accumulation of and proteinuria are by increased expression of growth factors as A.S. M. W. J. Am. Soc. Nephrol. 2001; 12: PubMed Google Scholar) and matrix as W. Full Text PDF PubMed Scopus Google we the expression of and in the There was a in and a in expression in the kidneys of C57BL/6J mice compared with those of mice In contrast, there were no changes in the A/J mice a in the of and of PAI-1, VEGF, and in to determine a role for increased renal expression of in the increased renal lipid accumulation as a of HFD, we performed in control and SREBP-1c–/– mice with SREBP-1c–/– mice are in and not The of the first of results in a of the J. J. Biol. Chem. 2002; 277: Full Text Full Text PDF PubMed Scopus Google Scholar). The of SREBP-1c–/– mice is described in with mice, SREBP-1c–/– mice levels of triglyceride and with the previous J. J. Biol. Chem. 2002; 277: Full Text Full Text PDF PubMed Scopus Google Scholar). There was no expression of in the kidneys of SREBP-1c–/– mice, but there were increases in renal levels of of expression in and SREBP-2 by and of In mice was HFD in renal SREBP-1 and SREBP-2 expression as well as in renal triglyceride accumulation In SREBP-1c–/– mice with HFD the significant in renal triglyceride accumulation seen in mice was also HFD to the renal expression of SREBP-2 that mediates cholesterol synthesis To determine the role of in renal we the renal levels of PAI-1, VEGF, and type IV and fibronectin, all of which have been in glomerulosclerosis and proteinuria. that the increased levels of those by HFD in mice were significantly in SREBP-1c–/– mice of of and SREBP-1c–/– cholesterol in a and cholesterol in the kidneys of and SREBP-1c–/– with with with in a levels of PAI-1, VEGF, type IV collagen, and fibronectin in the kidneys of and SREBP-1c–/– mice with with with IV with with with in a The purpose of study was to the role of renal lipid metabolism in renal disease. there were altered renal lipid metabolism and lipid accumulation associated with renal disease in diet-induced obesity SREBPs and their lipid synthesis were involved in renal lipid accumulation and they in the pathogenesis of renal disease by the of SREBP-1c–/– mice. of metabolic syndrome as obesity, hyperglycemia, and hyperinsulinemia in C57BL/6J mice. Our results also that in C57BL/6J mice with HFD there were increased renal expression of VEGF, PAI-1, type IV collagen, and fibronectin, and the development of glomerulosclerosis and proteinuria. These changes are in with in a model with similar M. PubMed Scopus Google Scholar). A/J mice were resistant to the of HFD on C57BL/6J mice. HFD they exhibited of the of metabolic syndrome and no altered glomerulosclerosis proteinuria. The of C57BL/6J mice in the of HFD the important role of high of fat and in the development of metabolic syndrome and suggested the of obesity, hyperglycemia, and hyperinsulinemia in the pathogenesis of renal disease in metabolic The of diet and seen in A/J and C57BL/6J mice of disease seen in human as and which higher of obesity and type diabetes M. T. M. J. Am. Soc. Nephrol. PubMed Scopus Google Scholar, A.S. Full Text Full Text PDF PubMed Scopus Google Scholar, C. C. 2002; Full Text Full Text PDF PubMed Scopus Google Scholar). of study was that in C57BL/6J mice, but not in A/J mice, there were increased in the kidney and significantly higher renal of triglyceride and cholesterol compared with those mice with increased lipid accumulation renal lipid and SREBPs have been shown to be regulators of the of we there were diet-induced changes in renal SREBPs expression. that the expression of renal SREBP-1 and SREBP-2 was by the of their that fatty acid and cholesterol including ACC, FAS, and Although we not cell we have SREBP-1a, SREBP-1c, and SREBP-2 expression in glomerular mesangial glomerular and renal The of SREBP expression in the kidney has not been well Our results that fatty renal SREBP expression. In the of fatty acid is with saturated fatty The were in with studies high fat the expression of SREBPs in J. R. C. S. W. L. M. P. Full Text Full Text PDF PubMed Scopus Google Scholar, K. M. E. Diabetes. 54: PubMed Scopus Google Scholar). fatty diet has been shown to expression of SREBPs J. H. S. J. 2002; PubMed Scopus Google Scholar). this has not been in In study HFD hyperinsulinemia and in C57BL/6J mice. studies have suggested that in as M. N. M. H. Full Text Full Text PDF PubMed Scopus Google S. C. S. J. Biol. Chem. 2002; 277: Full Text Full Text PDF PubMed Scopus Google and Y. S. S. A. PubMed Scopus Google Scholar). that changes in renal SREBPs are to high in the in C57BL/6J mice. shown in previous increased renal expression of SREBP-1 in type diabetic (20Sun L. Halaihel N. Zhang W. Rogers T. Levi M. J. Biol. Chem. 2002; 277: 18919-18927Abstract Full Text Full Text PDF PubMed Scopus (274) Google Scholar) and well be a factor for SREBPs in this diet-induced obesity C57BL/6J mice. the of is in the same type diabetic a decline of expression was in Y. S. S. A. PubMed Scopus Google Scholar). of SREBPs and their expression in C57BL/6J mice suggested a of renal lipid synthesis by The also that the increased triglyceride and cholesterol accumulation also in fatty acid and cholesterol that levels for and involved in cholesterol and that mediates fatty acid were in kidneys of C57BL/6J mice. of fatty acid and cholesterol renal a major to the increased accumulation of renal triglyceride and cholesterol in C57BL/6J mice with including fatty acid be for increased renal lipid S. S. A. A. E. P. B. F. Diabetes. 2002; PubMed Scopus Google Scholar). is that HFD not fatty acid in The for a role of SREBPs in renal lipid accumulation and in the pathogenesis of glomerulosclerosis and proteinuria associated with diet-induced obesity, that of in renal triglyceride and the of VEGF, PAI-1, type IV collagen, and fibronectin, the factors that have been in glomerulosclerosis and proteinuria. These results are to previous work to that in mice SREBP-1a, in the of increases in serum cholesterol there was a of and resulting in increased renal triglyceride increased expression of growth VEGF, type IV collagen, and fibronectin, mesangial and proteinuria (20Sun L. Halaihel N. Zhang W. Rogers T. Levi M. J. Biol. Chem. 2002; 277: 18919-18927Abstract Full Text Full Text PDF PubMed Scopus (274) Google Scholar). of SREBPs resulting in in renal lipid metabolism and renal lipid accumulation play a role in the nephropathy associated with diet-induced obesity. There is to the role of lipid metabolism in renal disease. has been that of cholesterol synthesis by and of triglyceride synthesis by diabetic and renal disease Y. J. Am. Soc. Nephrol. 2004; 15: 2801-2815Crossref PubMed Scopus (158) Google Scholar, S. R. Am. J. Med. PubMed Scopus Google Scholar, S. A. A. Am. J. Full Text Full Text PDF PubMed Scopus Google Scholar). recent of several studies in diabetic and human subjects with glomerulosclerosis and proteinuria that with significantly the decline in glomerular 2001; Full Text Full Text PDF PubMed Scopus Google Scholar). The and of lipids per se in kidney cell have also been demonstrated in cell in renal mesangial and in have shown that of these with low low results in increases in and cholesterol and causes of the growth including growth and growth factor Y. H. N. Full Text Full Text PDF PubMed Google proteins Full Text PDF PubMed Scopus Google cytokines, including and Y. H. N. Full Text Full Text PDF PubMed Google including and vascular cell R. Metab. 1996; Google Scholar). In results that an HFD to C57BL/6J mice, which are to diet-induced obesity, renal expression of the factors SREBP-1 and SREBP-2 and expression of their involved in renal fatty acid and cholesterol These changes are associated with increased renal accumulation of triglyceride and cholesterol and the development of glomerulosclerosis and proteinuria. In SREBP-1c–/– mice, of renal triglyceride and increased expression of PAI-1, VEGF, and proteins are in this model of diet-induced obesity, an important role in of renal lipid accumulation and the pathogenesis of glomerulosclerosis and proteinuria.
Jiang et al. (Wed,) studied this question.
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